Cardiovascular disease is the leading cause of death in the United States, with the incidence of cardiovascular disease increasing rapidly after 60 years of age. A primary risk factor for cardiovascular disease is hypertension, which also increases in prevalence in older individuals. Nitric oxide (NO) induced vasodilatation is reduced with age, resulting in increased blood pressure and reduced limb blood flow, particularly in light of the increased muscle sympathetic tone in older individuals. Impaired production of NO is also associated with peripheral vascular disease, insulin resistance, and Type 2 diabetes. However, there is some evidence that exercise training improves NO induced limb blood flow response at rest. The effect of exercise on the content of endothelial nitric oxide synthase (eNOS), the key enzyme in NO production, has not been investigated in muscle in vivo in humans. We hypothesize that there are reductions in eNOS expression and increases in muscle sympathetic tone in older individuals, resulting in reduced nitric oxide dependent skeletal muscle nutritive blood flow and alterations in muscle metabolism; furthermore, these age-associated NO-mediated changes can be counteracted, or reversed, by endurance exercise training. We will investigate 24 (20-30 yr) sedentary individuals (men and women), as well as 24 sedentary older (60-70 yr) individuals (men and women) in the sedentary state, as well as after one day and seven days of endurance exercise training. Ten of these sedentary older individuals will also be studied after an additional seven weeks of endurance training. A muscle biopsy will be taken to measure eNOS content, and nutritive skeletal muscle blood flow will be monitored using microdialysis under resting conditions. These investigations will determine if endurance exercise improves nitric oxide dependent nutritive blood flow in skeletal muscle at rest, and will determine if this improvement is associated with increases in eNOS in skeletal muscle biopsy samples. The mediation of NO-dependent vasodilation by muscle sympathetic tone, endothelin, and prostacyclin will also be investigated. The long-term objectives of these investigations are: 1) to identify mechanisms responsible for a reduced nitric oxide-dependent vasodilatation in older men and women and 2) to find practical means of reversing vasodilator decrements in older men and women, thereby reducing the incidence of cardiovascular-related diseases in this population.